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Embryonic stem cells (ESCs) have the ability to proliferate indefinitely in culture, and to differentiate into all embryonic lineages. Although the transcriptional program that coordinates pluripotency has been progressively unveiled during the past few years, the signalling pathways that regulate early differentiation events are not completely understood. We have recently described that CnAbeta1, an alternative splicing variant of the phosphatase calcineurin, enhances muscle regeneration and improves cardiac function after myocardial infarction. CnAbeta1 lacks the autoinhibitory domain typical of calcineurin, and instead has a unique C-terminal domain with no similarity to any known protein. Unlike other calcineurin isoforms, CnAbeta1 has no impact on NFAT-regulated genes and instead activates the Akt pathway. CnAbeta1 is strongly expressed in stem and progenitor cells, although its role in these cells is unknown. We found that CnAbeta1 downregulation had no effect on ESC pluripotency. However, CnAbeta1 depletion in mESCs during the first 48 hours of differentiation specifically affected differentiation towards the cardiac mesoderm lineage promoting hematopoietic differentiation. In contrast, CnAbeta1 1 overexpression promoted cardiac differentiation. Our results suggest that CnAbeta1 1 regulates mESC differentiation through the control of the Akt/GSK3 signalling pathway.To determine the role of CnAbeta1 in the adult heart, we developed cardiac-specific CnAbeta1 transgenic mice overexpressing CnAbeta1 specifically in cardiomyocytes and CnAbeta1Δi12 knockout mice that lack CnAbeta1's unique C-terminal domain. We found that CnAbeta1Δi12 mice show increased cardiac hypertrophy in response to trans-aortic banding, whereas transgenic mice overexpressing CnAbeta1 have decreased hypertrophy and fibrosis, and improved cardiac function. Together, these results suggest that CnAbeta1 is implicated in early cardiac differentiation, and that it reduces pathological cardiac hypertrophy in the adult heart. [ABSTRACT FROM PUBLISHER]

Background: An accurate evaluation of the degree of sedation is mandatory to adjust the dosage of sedative drugs., Objectives: To determine the correlation between head height above the ground and ataxia degree in horses sedated with detomidine and the correlation existing between accelerometric variables and both parameters., Study Design: Retrospective study., Methods: Twelve horses were given 0.01 mg/kg of detomidine hydrochloride iv. Measured accelerometric parameters, with one accelerometer positioned between both sacral tuberosities, included speed, stride frequency and length, regularity, dorsoventral, longitudinal, mediolateral and total accelerometric activities, relative force index and dorsoventral, longitudinal and mediolateral parts of the accelerometric activities. Head height above the ground (cm) and subjective ataxia degree were also measured. Baseline values (-15 min) and values measured 5 and 15 min after the injection and then every 15 min for a period of 2 h were obtained., Results: There was a negative and strong correlation between head height above the ground and ataxia degree (Pearson r = -0.78, p < 0.001), particularly during the first 45 min. A significant correlation was found between head height above the ground and almost all accelerometric parameters. This correlation was very strong with stride frequency, regularity and dorsoventral and total accelerometric activities in both cases, but for ataxia, also with total accelerometric activity., Main Limitations: Experimental conditions may not represent real clinical situations., Conclusions: Stride frequency and regularity are the most reliable parameters to determine degree of sedation and are related to the sedation produced. Ataxia should not be considered a separate property of sedation and does not need to be assessed separately to the depth of sedation., (© 2024 The Author(s). Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Pulmonary hypertension (PH) can affect both pulmonary arterial tree and cardiac function, often leading to right heart failure and death. Despite the urgency, the lack of understanding has limited the development of effective cardiac therapeutic strategies. Our research reveals that MCJ modulates mitochondrial response to chronic hypoxia. MCJ levels elevate under hypoxic conditions, as in lungs of patients affected by COPD, mice exposed to hypoxia, and myocardium from pigs subjected to right ventricular (RV) overload. The absence of MCJ preserves RV function, safeguarding against both cardiac and lung remodeling induced by chronic hypoxia. Cardiac-specific silencing is enough to protect against cardiac dysfunction despite the adverse pulmonary remodeling. Mechanistically, the absence of MCJ triggers a protective preconditioning state mediated by the ROS/mTOR/HIF-1α axis. As a result, it preserves RV systolic function following hypoxia exposure. These discoveries provide a potential avenue to alleviate chronic hypoxia-induced PH, highlighting MCJ as a promising target against this condition.

Stress leukogram includes eosinopenia as one of its main markers (neutrophilia, eosinopenia, lymphopenia, and mild monocytosis). Cortisol is the main stress biomarker, which is also strongly correlated with the severity of gastrointestinal diseases. This study aimed to determine the relationship between salivary cortisol and the eosinophil cell count (EC) in equids with abdominal pain. To do this, 39 horses with abdominal pain referred to an emergency service were included. All samples were taken on admission, and several parameters and clinical data were included. Equids were classified according to the outcome as survivors and non-survivors. Non-surviving equids presented higher salivary cortisol concentrations (Non-Survivors: 1.580 ± 0.816 µg/dL; Survivors 0.988 ± 0.653 µg/dL; p < 0.05) and lower EC (Non-Survivors: 0.0000 × 10 3 /µL (0.000/0.0075); Survivors: 0.0450 × 10 3 /µL (0.010/0.1825); p < 0.01). In addition, the relationship between salivary cortisol concentration, EC, and the WBC was determined. Only a strong correlation (negative) was observed between cortisol and EC (r = -0.523, p < 0.01). Since cortisol is not an analyte that can be measured routinely in clinical settings such as emergencies, the EC could be a good alternative. While the results are promising, further studies are needed before EC can be used confidently in routine practice to predict survival in cases of abdominal pain.

Introduction: Removal of poorly perfused capillaries by pruning contributes to remodeling the microvasculature to optimize oxygen and nutrient delivery. Blood flow drives this process by promoting the intravascular migration of endothelial cells in developing networks, such as in the yolk sac, zebrafish brain or postnatal mouse retina. Methods: In this study, we have implemented innovative tools to recognize capillary pruning in the complex 3D coronary microvasculature of the postnatal mouse heart. We have also experimentally tested the impact of decreasing pruning on the structure and function of this network by altering blood flow with two different vasodilators: losartan and prazosin. Results: Although both drugs reduced capillary pruning, a combination of experiments based on ex vivo imaging, proteomics, electron microscopy and in vivo functional approaches showed that losartan treatment resulted in an inefficient coronary network, reduced myocardial oxygenation and metabolic changes that delayed the arrest of cardiomyocyte proliferation, in contrast to the effects of prazosin, probably due to its concomitant promotion of capillary expansion. Discussion: Our work demonstrates that capillary pruning contributes to proper maturation and function of the heart and that manipulation of blood flow may be a novel strategy to refine the microvasculature and improve tissue perfusion after damage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Santamaría, Cruz-Caballero, Gkontra, Jiménez-Montiel, Clemente, López, Villalba-Orero, Vázquez, Hutloff, Lara-Pezzi and Arroyo.)

Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production 1,2 . This adaptation is triggered in part by post-partum environmental changes 3 , but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors 4 (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA-RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Cardiac cine magnetic resonance imaging (MRI) can be considered the optimal criterion for measuring cardiac function. This imaging technique can provide us with detailed information about cardiac structure, tissue composition and even blood flow, which makes it highly used in medical science. But due to the image time acquisition and several other factors the MRI sequences can easily get corrupted, causing radiologists to misdiagnose 40 million people worldwide each and every single year. Hence, the urge to decrease these numbers, researchers from different fields have been introducing novel tools and methods in the medical field. Aiming to the same target, we consider in this work the application of the higher order dynamic mode decomposition (HODMD) technique. The HODMD algorithm is a linear method, which was originally introduced in the fluid dynamics domain, for the analysis of complex systems. Nevertheless, the proposed method has extended its applicability to numerous domains, including medicine. In this work, HODMD in used to analyze sets of MR images of a heart, with the ultimate goal of identifying the main patterns and frequencies driving the heart dynamics. Furthermore, a novel interpolation algorithm based on singular value decomposition combined with HODMD is introduced, providing a three-dimensional reconstruction of the heart. This algorithm is applied (i) to reconstruct corrupted or missing images, and (ii) to build a reduced order model of the heart dynamics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein-protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturbing AS patterns., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Increasing evidence has pointed to the important function of T cells in controlling immune homeostasis and pathogenesis after myocardial infarction (MI), although the underlying molecular mechanisms remain elusive. In this study, a broad analysis of immune markers in 283 patients revealed significant CD69 overexpression on Tregs after MI. Our results in mice showed that CD69 expression on Tregs increased survival after left anterior descending (LAD) coronary artery ligation. Cd69-/- mice developed strong IL-17+ γδT cell responses after ischemia that increased myocardial inflammation and, consequently, worsened cardiac function. CD69+ Tregs, by induction of AhR-dependent CD39 ectonucleotidase activity, induced apoptosis and decreased IL-17A production in γδT cells. Adoptive transfer of CD69+ Tregs into Cd69-/- mice after LAD ligation reduced IL-17+ γδT cell recruitment, thus increasing survival. Consistently, clinical data from 2 independent cohorts of patients indicated that increased CD69 expression in peripheral blood cells after acute MI was associated with a lower risk of rehospitalization for heart failure (HF) after 2.5 years of follow-up. This result remained significant after adjustment for age, sex, and traditional cardiac damage biomarkers. Our data highlight CD69 expression on Tregs as a potential prognostic factor and a therapeutic option to prevent HF after MI.

In this work, we study in detail the performance of Higher Order Dynamic Mode Decomposition (HODMD) technique when applied to echocardiography images. HODMD is a data-driven method generally used in fluid dynamics and in the analysis of complex non-linear dynamical systems modeling several complex industrial applications. In this paper we apply HODMD, for the first time to the authors knowledge, for patterns recognition in echocardiography, specifically, echocardiography data taken from several mice, either in healthy conditions or afflicted by different cardiac diseases. We exploit the HODMD advantageous properties in dynamics identification and noise cleaning to identify the relevant frequencies and coherent patterns for each one of the diseases. The echocardiography datasets consist of video loops taken with respect to a long axis view (LAX) and a short axis view (SAX), where each video loop covers at least three cardiac cycles, formed by (at most) 300 frames each (called snapshots). The proposed algorithm, using only a maximum quantity of 200 snapshots, was able to capture two branches of frequencies, representing the heart rate and respiratory rate. Additionally, the algorithm provided a number of modes, which represent the dominant features and patterns in the different echocardiography images, also related to the heart and the lung. Six datasets were analyzed: one echocardiography taken from a healthy subject and five different sets of echocardiography taken from subjects with either Diabetic Cardiomyopathy, Obesity, SFSR4 Hypertrophy, TAC Hypertrophy or Myocardial Infarction. The results show that HODMD is robust and a suitable tool to identify characteristic patterns able to classify the different pathologies studied., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cardiac function and morphology by mouse fetal echocardiography can be assessed by scanning the uterus extracted from the abdominal cavity (trans-uterine ultrasound) or the womb (trans-abdominal ultrasound). Advantages of trans-abdominal ultrasound include (1) non-invasive longitudinal analysis at different stages, reducing animal use; and (2) maintenance of natural environment, diminishing perturbations on functional parameters, which are more frequent in trans-uterine conditions. Here we describe both approaches, explaining how to identify congenital cardiac defects and defining the correlation between echocardiography findings and histological analysis. For complete details on the use and execution of this protocol, please refer to (Menendez-Montes et al., 2016) and (Menendez-Montes et al., 2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Heart diseases are associated with changes in the biomechanical properties of the myocardial wall. However, there is no modality available to assess myocardial stiffness directly. Brillouin microspectroscopy (mBS) is a consolidated mechanical characterization technique, applied to the study of the viscoelastic and elastic behavior of biological samples and may be a valuable tool for assessing the viscoelastic properties of the cardiac tissue. In this work, viscosity and elasticity were assessed using mBS in heart samples obtained from healthy and unhealthy mice (n = 6 per group). Speckle-tracking echocardiography (STE) was performed to evaluate heart deformation. We found that mBS was able to detect changes in stiffness in the ventricles in healthy myocardium. The right ventricle showed reduced stiffness, in agreement with its increased compliance. mBS measurements correlated strongly with STE data, highlighting the association between displacement and stiffness in myocardial regions. This correlation was lost in pathological conditions studied. The scar region in the infarcted heart presented changes in stiffness when compared to the rest of the heart, and the hypertrophied left ventricle showed increased stiffness following aortic stenosis, compared to the right ventricle. We demonstrate that mBS can be applied to determine myocardial stiffness, that measurements correlate with functional parameters and that they change with disease., (© 2021. The Author(s).)

Objective: To determine demographic, preoperative and anaesthesia-related variables that may be associated with unsatisfactory recovery quality in horses undergoing emergency abdominal surgery (colic) in an equine teaching hospital., Study Design: Retrospective case series., Animals: A total of 313 horses., Methods: The anaesthetic records of horses admitted for surgical treatment of colic between 2005 and 2018 were examined. Overall quality of recovery was assessed as dangerous, poor, fair, good or excellent. The following categories were constructed as a dichotomic variable: unsatisfactory recovery (poor and dangerous recoveries) and satisfactory recovery (excellent, good and fair recoveries). Univariable and multivariable analyses were performed to evaluate the association between all studied variables and recovery., Results: All recoveries were unassisted. Unsatisfactory recovery quality totalled 17.2% (3.5% and 13.7% were dangerous and poor recoveries, respectively), whereas satisfactory recoveries totalled 82.8% (26.2%, 40.9% and 15.7% were fair, good and excellent recoveries, respectively). Univariable analysis showed that unsatisfactory recoveries were associated with high preoperative packed cell volume, pain behaviour, poor premedication and induction quality, high intraoperative mean heart rate, low mean arterial blood pressure, dobutamine dose ≥1.5 μg kg -1 minute -1 , non-administration of romifidine, long anaesthesia time and prolonged time to stand. The multivariable model showed that factors strongly associated with unsatisfactory recovery quality were dobutamine dose ≥1.5 μg kg -1 minute -1 [adjusted odds ratio (AOR) = 6.60; 95% confidence interval (CI), 2.91-14.96], poor premedication quality (AOR=4.60; 95% CI, 1.73-12.23) and a time to stand > 70 minutes (AOR=2.59; 95% CI, 1.13-5.91)., Conclusions and Clinical Relevance: Our study shows that high dobutamine requirements, poor premedication quality and a prolonged time to stand are risk factors for unsatisfactory recovery quality in horses undergoing anaesthesia for colic surgery. Addressing these factors may enable clinicians to improve the quality of recovery phase., (Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

[Figure: see text].

Background: Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice., Methods: TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed., Results: TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P =0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P =0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice., Conclusions: Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.

Standing surgery under sedation reduces anesthetic-related mortality in horses. Medetomidine, alone and combined with morphine in a constant rate infusion (CRI), has been described for standing surgery but their cardiorespiratory, sedative and antinociceptive effects have never been compared. The addition of ketamine could improve analgesia in these procedures with minimal cardiorespiratory consequences. The objectives were to compare the cardiorespiratory effects, quality of sedation, antinociception and ataxia produced by administration of a medetomidine-based CRI with morphine, ketamine or both, in standing horses. A prospective, blind, randomized crossover, experimental design with six healthy adult horses was performed, in which four treatments were administered to all horses with at least two weeks of washout period: medetomidine (M); medetomidine and ketamine (MK); medetomidine and morphine (MMo); and medetomidine, morphine and ketamine (MMoK). Dosages were the same in all treatment groups: medetomidine at 5 µg/kg bwt followed by 5 µg/kg bwt/h, ketamine at 0.4 mg/kg/h and morphine at 50 µg/kg bwt, followed by morphine 30 µg/kg bwt/h. Drug infusions were maintained for 120 min. Cardiorespiratory variables, sedation degree and antinociceptive effects were evaluated during the procedure. All combinations produced similar sedation and antinociceptive effects and no clinically relevant alterations in cardiorespiratory variables occurred. Medetomidine CRI combined with morphine, ketamine or both are suitable and safe protocols for standing sedation in horses and the addition of morphine and/or ketamine did not cause any negative effect but no improving effect on sedation and antinociception was detected.

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy ( Mmp14 f/f : Lyz2 -Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14 -deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process., Competing Interests: LA, ÁS, AP, PG, PG, VN, CC, MC, MV, JI, DG, AA, MR No competing interests declared, (© 2020, Alonso-Herranz et al.)

Background: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5., Methods: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter., Results: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition., Conclusions: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.

A 2-day-old filly was referred to the hospital with abdominal pain and constipation. The foal presented tachycardia, tachypnea, hypoxemia, hyperlactatemia, and abdominal distension. Meconium impaction was diagnosed, and the filly underwent abdominal surgery. Diazepam and butorphanol were administered for anesthesia premedication, but sedative effects were mild. Xylazine was used to enhance sedation and ketamine was subsequently administered for induction. The foal showed swallow reflex and head movement when intubation was attempted. Consequently, isoflurane on oxygen was provided via an anesthetic face mask. After intubation, the foal was connected to the anesthetic machine and monitored. The electrocardiogram revealed accelerated idioventricular rhythm, characterized by atrioventricular isorhythmic dissociation with monomorphic wide QRS complexes. Lidocaine was administered but the arrhythmia persisted during anesthesia and was spontaneously corrected once the isoflurane was discontinued at the end of the procedure. The foal recovered from anesthesia without complications and no further cardiac events were observed before the patient being discharged. Accelerated idioventricular rhythm likely resulted from administration of isoflurane to a foal presenting hypoxemia, a condition that exacerbates the risk of arrhythmia. Proper management of this abnormal rhythm is crucial as inappropriate treatments may worsen the arrhythmia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rationale: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored., Objective: To investigate the role of SRSF3 in cardiac function., Methods and Results: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation., Conclusions: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.

Background: In response to pressure overload, the heart develops ventricular hypertrophy that progressively decompensates and leads to heart failure. This pathological hypertrophy is mediated, among others, by the phosphatase calcineurin and is characterized by metabolic changes that impair energy production by mitochondria., Objectives: The authors aimed to determine the role of the calcineurin splicing variant CnAβ1 in the context of cardiac hypertrophy and its mechanism of action., Methods: Transgenic mice overexpressing CnAβ1 specifically in cardiomyocytes and mice lacking the unique C-terminal domain in CnAβ1 (CnAβ1 Δi12 mice) were used. Pressure overload hypertrophy was induced by transaortic constriction. Cardiac function was measured by echocardiography. Mice were characterized using various molecular analyses., Results: In contrast to other calcineurin isoforms, the authors show here that cardiac-specific overexpression of CnAβ1 in transgenic mice reduces cardiac hypertrophy and improves cardiac function. This effect is mediated by activation of serine and one-carbon metabolism, and the production of antioxidant mediators that prevent mitochondrial protein oxidation and preserve ATP production. The induction of enzymes involved in this metabolic pathway by CnAβ1 is dependent on mTOR activity. Inhibition of serine and one-carbon metabolism blocks the beneficial effects of CnAβ1. CnAβ1 Δi12 mice show increased cardiac hypertrophy and declined contractility., Conclusions: The metabolic reprogramming induced by CnAβ1 redefines the role of calcineurin in the heart and shows for the first time that activation of the serine and one-carbon pathway has beneficial effects on cardiac hypertrophy and function, paving the way for new therapeutic approaches., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Heart failure (HF) has become an epidemic and constitutes a major medical, social, and economic problem worldwide. Despite advances in medical treatment, HF prognosis remains poor. The development of efficient therapies is hampered by the lack of appropriate animal models in which HF can be reliably determined, particularly in mice. The development of HF in mice is often assumed based on the presence of cardiac dysfunction, but HF itself is seldom proved. Lung ultrasound (LUS) has become a helpful tool for lung congestion assessment in patients at all stages of HF. We aimed to apply this non-invasive imaging tool to evaluate HF in mouse models of both systolic and diastolic dysfunction., Methods and Results: We used LUS to study HF in a mouse model of systolic dysfunction, dilated cardiomyopathy, and in a mouse model of diastolic dysfunction, diabetic cardiomyopathy. LUS proved to be a reliable and reproducible tool to detect pulmonary congestion in mice. The combination of LUS and echocardiography allowed discriminating those mice that develop HF from those that do not, even in the presence of evident cardiac dysfunction. The study showed that LUS can be used to identify the onset of HF decompensation and to evaluate the efficacy of therapies for this syndrome., Conclusions: This novel approach in mouse models of cardiac disease enables for the first time to adequately diagnose HF non-invasively in mice with preserved or reduced ejection fraction, and will pave the way to a better understanding of HF and to the development of new therapeutic approaches., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.)